1. Field of the Invention
This invention relates to 2-[1H-benzimidazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetamides and 2-[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetamides, their salts, pharmaceutical compositions containing them, and their use as kinase inhibitors and in the treatment of cancer.
2. Description of the Related Art
As discussed by Mortlock et al., “Progress in the Development of Selective Inhibitors of Aurora Kinases”, Curr. Topics Med. Chem. 2005, 5, 199-213, and Carvajal et al., “Aurora Kinases: New Targets for Cancer Therapy”, Clin. Cancer Res. 2006, 12, 6869-6875, the Aurora family of kinases are involved in the regulation of mitosis. Two of the three human Aurora kinases, Aurora A and Aurora B, are frequently overexpressed in human tumors, while the Aurora A gene itself is amplified in many tumors. There has thus been considerable interest in the development of inhibitors of Aurora kinases as anticancer compounds for the treatment of both solid malignancies (e.g., colorectal, lung, breast, pancreatic, and bladder cancer) and hematological malignancies (e.g., acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), Hodgkin's and non-Hodgkin's lymphomas, and myelodysplastic syndrome (MDS)). A number of compounds have reached clinical trials, including Vertex and Merck's VX-680/MK-0457, which reached Phase II clinical studies but has now been discontinued and replaced in development by a later compound, VX-689 (MK-5108); Astex's AT9283; Astra Zeneca's AZD-1152; Entremed's ENMD-2076 and ENMD-981693; Millennium's MLN-8054 and MLN-8237; Nerviano's PHA-739358; Rigel's R763; Sunesis's SNS-314; and others.
As discussed by Ferrera and Kerbel, “Angiogenesis as a therapeutic target”, Nature 2005, 438, 967-974, and more recently by Ellis and Hicklin, “VEGF-targeted therapy: mechanisms of anti-tumour activity”, Nature Rev. Cancer 2008, 8, 579-591, the inhibition of angiogenesis by the targeting of VEGF-A and its receptors is considered to be a highly promising strategy for cancer treatment. Two inhibitors of VEGFR2 kinase; sunitinib (Pfizer's Sutent®) and sorafenib (Bayer/Onyx's Nexavar®) are already approved in the US for the treatment of kidney cancer, while sunitinib is also approved for the treatment of gastro-intestinal cancer. A number of other VEGFR2 kinase-inhibiting compounds are in advanced development, among them GSK's pazopanib, Novartis's vatalinib, Pfizer's axitinib, Astra Zeneca's vandetanib, and others, for both solid (e.g. breast, ovarian, lung, and colorectal) and hematological malignancies. Also, bevacizumab (Genentech's Avastin), although not a VEGFR2 kinase inhibitor but an anti-VEGF antibody, is seeing use in brain cancer, suggesting that VEGFR2 kinase inhibitors may also find use in it, as in all other solid tumors.
Many of these compounds, whether the Aurora kinase inhibitors or the VEGFR inhibitors mentioned in the above paragraphs, are not specific inhibitors of the named kinases, but rather are selective inhibitors of the named kinases, also acting on other kinases. For example, sorafenib and sunitinib also have significant activity against Raf kinase and other kinases, and Cyclacel's CYC116 has been reported to inhibit Aurora kinases A, B, and C, VEGFR2 kinase, and Flt3 with IC50s all below 100 nM.
It would be desirable to develop compounds that are potent inhibitors of Aurora kinase, also inhibiting VEGFR2 kinase, as anticancer agents.
The disclosures of the documents referred to in this application are incorporated into this application by reference.